Analysis of stop-gain and frameshift variants in human innate immunity genes

Abstract

Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to the innate immunity genes we first evaluated 17764 stop-gain and 13915 frameshift variants from the NHLBI Exome Sequencing Project and 1000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and non-sense mediated decay were found to correlate with variant allele frequency and validated with gene expression data.We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against OMIM disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing genebased pathogenicity scores. Author summaryThere are well characterized severe immunodeficiencies associated with loss-of-function variants in innate immunity genes. Genome sequencing projects identify rare stop-gain and frameshift variants in innate immunity genes whose phenotype is uncharacterized. Current methods to estimate the severity of rare stop-gains and frameshifts are based on evolutionary conservation of the gene and the likelihood for redundancy in its function. These parameters are not always applicable to innate immunity genes. We evaluated sequence-level characteristics of more than 30'000 stop-gains and frameshifts and prioritized variants according to their predicted functional consequences. Our scoring approach complements existing tools in the prediction of innate immunity OMIM disease variants and associates with functional readouts such as gene expression. In this framework, we show that many individuals do carry high pathogenicity peer-reviewed)

Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage

“…A number of gene-and variant-level methods have been proposed for the analysis of WES data to select candidate variants in rare Mendelian disorders and more common traits (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). These analyses benefit from the use of additional information, such as familial linkage, homozygosity rate, and ethnic background, which are commonly used in the study of inherited diseases (14)(15)(16)(17).…”

Scoring of pathogenic non-coding variants in Mendelian diseases through supervised learning on ancient, recent and ongoing purifying selection signals in human

“…Primate dn/ds ratios (i.e. the ratio between the number of nonsynonymous substitutions and the number of synonymous substitutions) were taken from 45 . Low dn/ds values reflect purifying selection, while high dn/ds values are indicative of positive selection.…”

“…Inter-species (Primates) C dN/dS Primate dN/dS ratio, providing a measure of the coding-sequence conservation across primates 45 On-going in human C pLI Probability of being loss-of-function intolerant (intolerant of heterozygous and homozygous loss-of-function variants), assessed from the ExAC database. 31 On-going in human C RVIS percentile…”

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

“…Moreover, the LoF may apply selectively to one or a subset of isoforms of a given gene, but not others (e.g. if the exon carrying the premature stop is spliced out for a specific set of alternative transcripts) (5). Finally, there are at least 400 discernible cell types in the human body (6), and the mutant transcript may be expressed in only a limited number of tissues.…”